But recent discoveries in cell and molecular biology, combined with the techniques of biomedical engineering, are creating new options for more effective drug delivery with fewer side effects. One novel approach being explored by biomedical engineer Douglas Goetz involves targeting drugs to specific sites along blood vessel walls.

He is applying principles of biomechanics to solve a problem posed by two competing forces: the attraction between two molecules and the shear forces of fluid flow that threaten to overpower the molecular attraction. The competition occurs inside blood vessels.

The inner lining of blood vessels is made up of endothelial cells. The surface of these cells is dotted with receptors that act as handles that other molecules, called ligands, can grab. Some of these receptors are only present at or near diseased tissue. The receptor E-selectin, for example, has been found at sites of inflammation, atherosclerosis and cancer, but not in normal vessels. This selectivity makes E-selectin an attractive drug target.

Here is how the strategy might work: Drugs for the damaged or diseased tissue would be placed in tiny capsules that would grab onto E-selectin. The encapsulated drug could be a small piece of DNA, a synthetic organic compound, or a protein, depending on the disease and treatment strategy.

The capsules themselves would be made of biodegradable polymers or materials similar to cell membranes and could range in size from slightly smaller than a blood cell (14 of which can fit in the 70-micrometer width of a human hair) to slightly larger than a protein (3,500 of which span a hair's width). Ligands for E-selectin would be placed on the outer surface of the capsules. The ligands would attach only to endothelial cells with E-selectin. Packaging drugs this way should maximize delivery to diseased tissue marked by E-selectin while minimizing delivery to healthy tissue.

"To rationally develop and optimize this promising therapeutic approach, it is important to understand the biophysics of targeted drug carrier interactions with the endothelium," says Goetz, Ph.D., an assistant professor in the Department of Biomedical Engineering at the University of Memphis. "These interactions are governed by physical processes, including reaction kinetics, adhesive mechanics, and transport, all of which lend themselves to a biomechanical engineering analysis.

"In designing the drug carriers, it is important to consider the bloodstream itself, which keeps things moving through the vessels," Goetz says. "Once the drug capsule locks onto E-selectin, it would also have to fight the current to avoid being swept downstream."

Several different ligands could be used to target E-selectin. One option could be the naturally occurring ligands for E-selectin that exist on white blood cells circulating in the bloodstream. White blood cells use these ligands to grab onto E-selectin present on endothelial cells at sites of tissue damage or infection. In this way, white blood cells are selectively drawn to sites of tissue injury, where they work to repair the damage and fight infection.

Goetz is focusing on precisely which white blood cell ligands grab onto E-selectin. One candidate is a molecule called PSGL-1. In collaboration with Francis Luscinskas of the Brigham and Women's Hospital, Daniel Greif of the University of Washington, and Raymond Camphausen of Genetics Institute, Goetz has demonstrated that PSGL-1 could, in fact, do the job.

In a series of experiments published recently in The Journal of Cell Biology, the researchers coated particles with a recombinant form of PSGL-1 and studied the interaction of these particles with endothelial cells under experimental conditions that mimic blood flow. The PSGL-1 particles readily attached to endothelial cells that were expressing E-selectin. The PSGL-1 particles did not, however, interact with control endothelial cells not expressing E-selectin.

"These results strongly suggest that PSGL-1 could be used to selectively target drug carriers to E-selectin presenting endothelial cells," Goetz says.

But binding is only part of the problem. PSGL-1 particles that attached to the endothelial cells did not hold their position, but instead were dragged slowly along the endothelial cell surface in the direction of the fluid flow. It appears that the bonding force between PSGL-1 and E-selectin was enough to slow the particles and keep them in contact with the endothelial cells but was not enough to fix them in one place. This finding illustrates the competition here between adhesive force and the force of flowing blood.

"Whether a ligand-coated drug carrier grabs onto a particular endothelial cell and what subsequently happens to the carrier is a function of a variety of factors, including the flow of the blood, the size of the carrier, the ligand coating the carrier, and the target receptor," Goetz says.

By a combination of experimental techniques and biochemical engineering analyses, Goetz and his colleagues hope to establish a set of principles concerning targeted drug carrier interactions with the endothelium. "Such information can be used to guide the rational and efficient development of therapeutic agents," he says.

Goetz was hired by the University of Memphis two years ago under a Special Opportunity Award, which created the Joint Program in Biomedical Engineering between the University of Memphis and the University of Tennessee at Memphis. Expanding biomedical engineering in Memphis will create opportunities for graduate students to become involved in the line of investigation that Goetz is pursuing.